JP2020500526A5 - - Google Patents

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JP2020500526A5
JP2020500526A5 JP2019529263A JP2019529263A JP2020500526A5 JP 2020500526 A5 JP2020500526 A5 JP 2020500526A5 JP 2019529263 A JP2019529263 A JP 2019529263A JP 2019529263 A JP2019529263 A JP 2019529263A JP 2020500526 A5 JP2020500526 A5 JP 2020500526A5
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pharmaceutical composition
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modulator
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JP7292204B2 (en
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また、本明細書に記載のようなタウモジュレーターの成分を含むおよび／またはタウモジュレーター（またはその成分）をコードするＡＡＶタウモジュレーター（例えば、リプレッサー）および／またはポリヌクレオチドの１つまたは複数を含むキットが提供される。キットは、細胞（例えば、ニューロン）、（例えば、例えばＣＳＦにおいてタウタンパク質を検出および／または定量化するための）試薬、および／または本明細書に記載のような方法を含むその使用のための説明書をさらに含んでいてもよい。
特定の実施形態では、例えば、以下が提供される：
（項目１）
微小管結合タンパク質タウ（ＭＡＰＴ）遺伝子の遺伝子モジュレーターであって、
該ＭＡＰＴ遺伝子の少なくとも１２個のヌクレオチドの標的部位に結合するＤＮＡ結合ドメイン、および
転写制御ドメインまたはヌクレアーゼドメイン
を含む遺伝子モジュレーター。
（項目２）
前記ＤＮＡ結合ドメインが、ジンクフィンガータンパク質（ＺＦＰ）、ＴＡＬ−エフェクタードメインタンパク質（ＴＡＬＥ）、または単鎖ガイドＲＮＡを含む、項目１に記載の遺伝子モジュレーター。
（項目３）
前記転写制御ドメインが、抑制ドメインまたは活性化ドメインを含む、項目１または項目２に記載の遺伝子モジュレーター。
（項目４）
項目１から３のいずれかに記載の遺伝子モジュレーターをコードするポリヌクレオチド。
（項目５）
項目４に記載のポリヌクレオチドを含む遺伝子送達ビヒクル。
（項目６）
ＡＡＶベクターを含む、項目５に記載の遺伝子送達ビヒクル。
（項目７）
項目１から３に記載の１つまたは複数の遺伝子モジュレーター、項目４に記載の１つまたは複数のポリヌクレオチド、および／または項目５または６に記載の１つまたは複数の遺伝子送達ビヒクルを含む医薬組成物。
（項目８）
前記遺伝子モジュレーターが、ヌクレアーゼドメインを含み、該遺伝子モジュレーターが、前記ＭＡＰＴ遺伝子を切断する、項目７に記載の医薬組成物。
（項目９）
切断された前記ＭＡＰＴ遺伝子に組み込まれるドナー分子をさらに含む、項目８に記載の医薬組成物。
（項目１０）
項目１から３に記載の１つまたは複数の遺伝子モジュレーター、項目４に記載の１つまたは複数のポリヌクレオチド、項目５または６に記載の１つまたは複数の遺伝子送達ビヒクル、および／または項目７から９のいずれかに記載の医薬組成物を含む単離細胞。
（項目１１）
対象のＭＡＰＴ発現を調節するための、項目１から３に記載の１つまたは複数の遺伝子モジュレーター、項目４に記載の１つまたは複数のポリヌクレオチド、項目５または６に記載の１つまたは複数の遺伝子送達ビヒクル、および／または項目７から９のいずれかに記載の医薬組成物の使用。
（項目１２）
ＭＡＰＴ発現が抑制される、項目１１に記載の使用。
（項目１３）
前記対象への投与が、脳室内、髄腔内、頭蓋内、静脈内、後眼窩的、または槽内である、項目１１または１２に記載の使用。
（項目１４）
前記対象中のＭＡＰＴ発現の抑制が、タウオパチーを処置および／または予防する、項目１１から１３のいずれかに記載の使用。
（項目１５）
前記対象中のタウの量が低減される、項目１１から１４のいずれかに記載の使用。
（項目１６）
項目１から３に記載の１つまたは複数の遺伝子モジュレーター、項目４に記載の１つまたは複数のポリヌクレオチド、項目５または６に記載の１つまたは複数の遺伝子送達ビヒクル、項目７から９のいずれかに記載の医薬組成物、および／または使用のための指示を含むキット。 It also comprises one or more of the AAV tau modulators (eg, repressors) and / or polynucleotides that contain and / or encode tau modulators (or components thereof) as described herein. A kit is provided. The kit includes cells (eg, neurons), reagents (eg, for detecting and / or quantifying tau protein in CSF, for example), and / or methods as described herein for its use. Additional instructions may be included.
In certain embodiments, for example, the following is provided:
(Item 1)
A gene modulator of the microtubule-associated protein tau (MAPT) gene
A DNA-binding domain that binds to the target site of at least 12 nucleotides of the MAPT gene, and
Transcription control domain or nuclease domain
Gene modulators including.
(Item 2)
The gene modulator according to item 1, wherein the DNA binding domain comprises a zinc finger protein (ZFP), a TAL-effector domain protein (TALE), or a single-stranded guide RNA.
(Item 3)
The gene modulator according to item 1 or item 2, wherein the transcription control domain includes an inhibitory domain or an activation domain.
(Item 4)
A polynucleotide encoding the gene modulator according to any one of items 1 to 3.
(Item 5)
A gene delivery vehicle comprising the polynucleotide according to item 4.
(Item 6)
The gene delivery vehicle of item 5, comprising an AAV vector.
(Item 7)
A pharmaceutical composition comprising one or more gene modulators according to items 1-3, one or more polynucleotides according to item 4, and / or one or more gene delivery vehicles according to item 5 or 6. Stuff.
(Item 8)
The pharmaceutical composition according to item 7, wherein the gene modulator contains a nuclease domain and the gene modulator cleaves the MAPT gene.
(Item 9)
The pharmaceutical composition according to item 8, further comprising a donor molecule that is integrated into the cleaved MAPT gene.
(Item 10)
From item 1-3, one or more gene modulators, item 4, one or more polynucleotides, item 5 or 6, one or more gene delivery vehicles, and / or item 7. An isolated cell containing the pharmaceutical composition according to any one of 9.
(Item 11)
One or more gene modulators of items 1-3, one or more polynucleotides of item 4, one or more of items 5 or 6 for regulating MAPT expression in a subject. Use of a gene delivery vehicle and / or the pharmaceutical composition according to any of items 7-9.
(Item 12)
The use according to item 11, wherein MAPT expression is suppressed.
(Item 13)
The use according to item 11 or 12, wherein the administration to the subject is intraventricular, intrathecal, intracranial, intravenous, retroorbital, or intracisional.
(Item 14)
The use according to any of items 11 to 13, wherein suppression of MAPT expression in the subject treats and / or prevents tauopathy.
(Item 15)
The use according to any of items 11-14, wherein the amount of tau in the subject is reduced.
(Item 16)
One or more gene modulators of items 1 to 3, one or more polynucleotides of item 4, one or more gene delivery vehicles of item 5 or 6, any of items 7-9. A kit containing the pharmaceutical composition according to the gene and / or instructions for use.

図７Ａ〜７Ｄは、ヒトｉＰＳＣ由来ニューロンでのｍＲＮＡ（ヒトタウおよびＺＦＰ）レベルを示す。図７Ａは、ヒトおよびマウスＭＡＰＴ標的部位（それぞれ左から右へ、配列番号３１、３２、および４８〜５１）の部分配列を示す模式図である。図７Ｂは、ＡＡＶベクターにより運搬される表示リプレッサーを表示投薬量で投与した１８日後のｉＰＳＣでのｍＲＮＡ発現を示すグラフを示す。図７Ｃは、表示プロモーターを有するＡＡＶベクターにより運搬される表示リプレッサー（５２３６６）を投与した１８日後のｉＰＳＣでのｍＲＮＡ発現を示すグラフを示す。図７Ｄは、ヒトｉＰＳＣ由来ニューロンにおいて例示的なＺＦＰ ＴＦを使用した一連のマイクロアレイプロットであり、ＺＦＰ ＴＦが高度に特異的であることを示す。細胞を、分析前に１９日間にわたって、ＺＦＰ−ＴＦドナーを含む１Ｅ５のＡＡＶ６に曝露した。7A-7D show mRNA (human tau and ZFP) levels in human iPSC-derived neurons. FIG. 7A is a schematic diagram showing partial sequences of human and mouse MAPT target sites (SEQ ID NOs: 31 , 32 , and 48-51 , respectively, from left to right ). FIG. 7B shows a graph showing mRNA expression on iPSCs 18 days after administration of the labeled repressor carried by the AAV vector at the labeled dosage. FIG. 7C shows a graph showing mRNA expression on iPSCs 18 days after administration of a display repressor (52366) carried by an AAV vector with a display promoter. FIG. 7D is a series of microarray plots using exemplary ZFP TFs in human iPSC-derived neurons, showing that ZFP TFs are highly specific. Cells were exposed to 1E5 AAV6 containing ZFP-TF donors for 19 days prior to analysis. 同上。Same as above. 同上。Same as above.

（実施例１）
ＭＡＰＴリプレッサー
本質的に米国特許第６，５３４，２６１号、米国特許出願公開第２０１５／００５６７０５号、第２０１１／００８２０９３号、第２０１３／０２５３０４０号、および第２０１５／０３３５７０８号に記載のように遺伝子操作されたおよそ１８５個のジンクフィンガータンパク質のスクリーニングを実施し、ＺＦＰをそれらのＭＡＰＴ標的部位に結合させた。マウスＭＡＰＴを標的とするジンクフィンガータンパク質５２２８８、５２３２２、５２３６４、５２３６６、５２３８９、５７８８０、５７８９０、および６５８８８（下記の表１〜３を参照）を、さらなる研究のために選択した。６５８８８に関して列挙されているホスフェート接触突然変異体は、以前に記載されている（例えば、米国特許出願第１５／６８５，５８０号を参照）。表１は、これらＺＦＰのＤＮＡ結合ドメインの認識ヘリックスおよびこれらＺＦＰの標的配列を示す。また、１セットのＺＦＰを、マウスおよびヒト遺伝子間で共有されるＭＡＰＴ配列を標的とするように製作した。それらは表２に示されている。表３は、親ＺＦＰ ＴＦ、および潜在的な非特異的ホスフェート接触を除去するためにＺＦＰ骨格を表示位置で突然変異させた誘導体ＺＦＰ ＴＦを示す。ＺＦＰは、標準的ＳＥＬＥＸ分析により評価したところ、それらの標的部位に結合することが示された。
表１：マウスＭＡＰＴ特異的リプレッサー設計
表２：ヒト／マウスＭＡＰＴ特異的リプレッサー設計
(Example 1)
MAPT Repressor Essentially a gene as described in US Pat. No. 6,534,261, US Patent Application Publication No. 2015/0056705, 2011/0082093, 2013/0253040, and 2015/0335708. Screening of approximately 185 engineered zinc finger proteins was performed and ZFP was bound to their MAPT target sites. Zinc finger proteins 52288, 52322, 52364, 52366, 52389, 57880, 57890, and 65888 (see Tables 1-3 below) targeting mouse MAPT were selected for further study. Phosphate contact variants listed for 65888 have been previously described (see, eg, US Patent Application No. 15 / 685,580). Table 1 shows the recognition helices of the DNA-binding domains of these ZFPs and the target sequences of these ZFPs. A set of ZFPs was also made to target MAPT sequences shared between mouse and human genes. They are shown in Table 2. Table 3 shows the parent ZFP TF and the derivative ZFP TF with the ZFP backbone mutated at the indicated position to eliminate potential non-specific phosphate contacts. ZFPs were evaluated by standard SELEX analysis and were shown to bind to their target sites.
Table 1: Mouse MAPT-specific repressor design
Table 2: Human / mouse MAPT-specific repressor design

骨格領域に突然変異を含むＺＦＰ−ＴＦタウリプレッサーを遺伝子操作した。表３には、例示的ＺＦＰ−ＴＦリプレッサー（およびそれらの親化合物）が表されている。こうした最適化されたＺＦＰ ＴＦでの結果（例えば、６５８８８〜５７８８０を比較して示した例示的な結果）によると、初代ニューロンでは、活性に影響を及ぼさずに特異性が劇的に（１０倍よりも大きく）向上したことが実証された（タウ抑制、図１Ｂを参照）。さらに、５７８８０親の２つの誘導体６５８８７および６５８８８を、ＢＯＤ１およびＭＯＳＰＤ１オフターゲットの抑制活性について、Ｎｅｕｒｏ２Ａ細胞で試験したところ（図１Ｄを参照）、ＺＦＰ骨格にホスフェート接触突然変異を含むタンパク質では、オフターゲット抑制が低減された。米国特許出願第１５／６８５，５８０号も参照されたい。
（実施例２）
マウスニューロンでのタウ抑制 A ZFP-TF tau repressor containing a mutation in the skeletal region was genetically engineered. Table 3 shows exemplary ZFP-TF repressors (and their parent compounds). According to the results of these optimized ZFP TFs (eg, exemplary results shown by comparing 65888-57880), primary neurons have a dramatic (10-fold) specificity without affecting activity. Demonstrated (greater than) improvement (tau suppression, see Figure 1B). In addition, two derivatives of 57880 parents, 658887 and 65888, were tested in Neuro2A cells for inhibitory activity on BOD1 and MOSPD1 off-targets (see Figure 1D) and off-targets for proteins containing a phosphate contact mutation in the ZFP backbone. Suppression was reduced. See also U.S. Patent Application No. 15 / 685,580.
(Example 2)
Tau suppression in mouse neurons

本明細書に記載のすべてのＺＦＰの標準的ＳＥＬＥＸ特異性分析に基づき、表２および３に列挙されているＺＦＰは、ヒトＭＡＰＴ配列の１つ（ＳＢＳ＃５７８９０およびＳＢＳ＃５２３６６の場合）または２つ（ＳＢＳ＃５７８８０の場合）の非保存的位置でのミスマッチを許容することが予測された（図７Ａ、それぞれ左から右へ、配列番号３１および３２、および４８〜５１を参照）。 Based on the standard SELEX specificity analysis of all ZFPs described herein, the ZFPs listed in Tables 2 and 3 are one of the human MAPT sequences (for SBS # 57890 and SBS # 52366) or 2 It was predicted to tolerate one (in the case of SBS # 57880) mismatches at non-conservative locations (Fig. 7A, left to right, see SEQ ID NOs: 31 and 32 , and 48-51 , respectively ).

Claims (19)

微小管結合タンパク質タウ（ＭＡＰＴ）遺伝子の遺伝子モジュレーターであって、
該ＭＡＰＴ遺伝子内の配列番号１〜６、３３、および４４〜４５のいずれかの少なくとも１２個のヌクレオチドの標的部位に結合するＤＮＡ結合ドメイン、および
転写制御ドメインまたはヌクレアーゼドメイン
を含む遺伝子モジュレーター。 A gene modulator of the microtubule-associated protein tau (MAPT) gene
A gene modulator comprising a DNA binding domain that binds to the target site of at least 12 nucleotides of any of SEQ ID NOs: 1-6, 33, and 44-45 within the MAPT gene, and a transcriptional regulatory or nuclease domain. 前記ＤＮＡ結合ドメインが、ジンクフィンガータンパク質（ＺＦＰ）、ＴＡＬ−エフェクタードメインタンパク質（ＴＡＬＥ）、または単鎖ガイドＲＮＡを含む、請求項１に記載の遺伝子モジュレーター。 The gene modulator according to claim 1, wherein the DNA binding domain comprises a zinc finger protein (ZFP), a TAL-effector domain protein (TALE), or a single-stranded guide RNA. 前記転写制御ドメインが、抑制ドメインまたは活性化ドメインを含む、請求項１または請求項２に記載の遺伝子モジュレーター。 The gene modulator according to claim 1 or 2, wherein the transcriptional control domain includes an inhibitory domain or an activation domain. 前記遺伝子モジュレーターが、ヒト細胞内のＭＡＰＴ遺伝子を調節する、請求項１から３のいずれか一項に記載の遺伝子モジュレーター。 The gene modulator according to any one of claims 1 to 3, wherein the gene modulator regulates a MAPT gene in human cells. 請求項１から４のいずれか一項に記載の遺伝子モジュレーターをコードするポリヌクレオチド。 A polynucleotide encoding the gene modulator according to any one of claims 1 to 4 . 請求項５に記載のポリヌクレオチドを含む遺伝子送達ビヒクル。 A gene delivery vehicle comprising the polynucleotide according to claim 5 . ＡＡＶベクターを含む、請求項６に記載の遺伝子送達ビヒクル。 The gene delivery vehicle according to claim 6 , which comprises an AAV vector. 請求項１から４のいずれか一項に記載の１つまたは複数の遺伝子モジュレーター、請求項５に記載の１つまたは複数のポリヌクレオチド、および／または請求項６または７に記載の１つまたは複数の遺伝子送達ビヒクルを含む医薬組成物。 One or more gene modulators according to any one of claims 1 to 4, one or more polynucleotides according to claim 5 , and / or one or more according to claims 6 or 7. A pharmaceutical composition comprising a gene delivery vehicle of. 前記遺伝子モジュレーターが、ヌクレアーゼドメインを含み、該遺伝子モジュレーターが、前記ＭＡＰＴ遺伝子を切断する、請求項８に記載の医薬組成物。 The pharmaceutical composition according to claim 8 , wherein the gene modulator contains a nuclease domain, and the gene modulator cleaves the MAPT gene. 切断された前記ＭＡＰＴ遺伝子に組み込まれるドナー分子をさらに含む、請求項９に記載の医薬組成物。 The pharmaceutical composition according to claim 9 , further comprising a donor molecule that integrates into the cleaved MAPT gene. 請求項１から４のいずれか一項に記載の１つまたは複数の遺伝子モジュレーター、請求項５に記載の１つまたは複数のポリヌクレオチド、請求項６または７に記載の１つまたは複数の遺伝子送達ビヒクル、および／または請求項８から１０のいずれか一項に記載の医薬組成物を含む単離細胞。 One or more gene modulators according to any one of claims 1 to 4, one or more polynucleotides according to claim 5 , one or more gene delivery according to claims 6 or 7. An isolated cell comprising a vehicle and / or the pharmaceutical composition according to any one of claims 8 to 10 . 対象のＭＡＰＴ発現を調節するための医薬の製造のための、請求項１から４のいずれか一項に記載の１つまたは複数の遺伝子モジュレーター、請求項５に記載の１つまたは複数のポリヌクレオチド、請求項６または７に記載の１つまたは複数の遺伝子送達ビヒクル、および／または請求項８から１０のいずれか一項に記載の医薬組成物の使用。 One or more gene modulators according to any one of claims 1 to 4, one or more polynucleotides according to claim 5 , for the manufacture of a medicament for regulating MAPT expression of interest. use of one or more gene delivery vehicles, and / or pharmaceutical composition according to any one of claims 8 to 10 according to claim 6 or 7. 請求項１から４のいずれか一項に記載の１つまたは複数の遺伝子モジュレーター、請求項５に記載の１つまたは複数のポリヌクレオチド、請求項６または７に記載の１つまたは複数の遺伝子送達ビヒクル、請求項８から１０のいずれか一項に記載の医薬組成物、および使用のための指示を含むキット。 One or more gene modulators according to any one of claims 1 to 4, one or more polynucleotides according to claim 5 , one or more gene delivery according to claims 6 or 7. vehicle, the pharmaceutical composition according to any one of claims 8 10, Oyo kits include instructions for for beauty use. 対象のＭＡＰＴ発現を調節するための、請求項１から４のいずれか一項に記載の１つまたは複数の遺伝子モジュレーターを含む組成物、請求項５に記載の１つまたは複数のポリヌクレオチドを含む組成物、請求項６または７に記載の１つまたは複数の遺伝子送達ビヒクルを含む組成物、および／または請求項８から１０のいずれか一項に記載の医薬組成物。 A composition comprising one or more gene modulators according to any one of claims 1 to 4, comprising one or more polynucleotides according to claim 5 for regulating MAPT expression of interest. The composition, the composition comprising one or more gene delivery vehicles according to claim 6 or 7, and / or the pharmaceutical composition according to any one of claims 8 to 10. ＭＡＰＴ発現が前記対象において抑制される、請求項１４に記載の組成物または医薬組成物。 The composition or pharmaceutical composition according to claim 14, wherein MAPT expression is suppressed in the subject. 前記組成物または医薬組成物が、脳室内、髄腔内、頭蓋内、静脈内、後眼窩的、または槽内で前記対象に投与されることを特徴とする、請求項１４または１５に記載の組成物または医薬組成物。 14. The composition according to claim 14 or 15, wherein the composition or pharmaceutical composition is administered to the subject intraventricularly, intrathecally, intracranial, intravenously, retroorbitally, or in a cistern. Composition or pharmaceutical composition. 前記対象中のＭＡＰＴ発現の抑制が、タウオパチーを処置および／または予防する、請求項１４から１６のいずれか一項に記載の組成物または医薬組成物。 The composition or pharmaceutical composition according to any one of claims 14 to 16, wherein suppression of MAPT expression in the subject treats and / or prevents tauopathy. 前記対象中のタウの量が低減される、請求項１４から１７のいずれか一項に記載の組成物または医薬組成物。 The composition or pharmaceutical composition according to any one of claims 14 to 17, wherein the amount of tau in the subject is reduced. 前記対象がヒトである、請求項１４から１８のいずれか一項に記載の組成物または医薬組成物。 The composition or pharmaceutical composition according to any one of claims 14 to 18, wherein the subject is a human.
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